Benjamin J. Shin

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas

OBJECT The purpose of this study was to analyze preoperative predictors of endocrinological remission following endonasal endoscopic resection of therapy-resistant prolactin-, growth hormone (GH)-, and adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas and to establish benchmarks for cure by using the most recent consensus criteria. METHODS The authors reviewed a prospective database of 86 consecutive functional pituitary adenomas that were resected by a purely endoscopic endonasal transsphenoidal technique. Extent of resection was evaluated on postoperative contrast-enhanced MR imaging. Endocrinological remission was defined according to the most recent consensus criteria. RESULTS The majority of functional adenomas (62.8%) were classified as macroadenomas (> 1 cm in maximum diameter), and 20.9% of lesions had invaded the cavernous sinus (CS) at the time of surgery. A gross-total resection was achieved in 75.6% of all patients. The rate of endocrinological remission differed between various types of functional adenomas. Cure rates were 92.3% (microadenomas) and 57.1% (macroadenomas) for prolactinomas, 75% (microadenomas) and 40% (macroadenomas) for GH-secreting tumors, and 54.5% (microadenomas) and 71.4% (macroadenomas) for ACTH-secreting tumors. Lower rates of cure occurred in GH-secreting macroadenomas due to a high rate of CS invasion, and in ACTH-secreting adenomas due to a high rate of lesions that were not visible on preoperative MR imaging. Whereas univariate analysis showed that macroadenoma, suprasellar, cavernous extension, or extent of resection correlated with cure, on multivariate analysis, only extent of resection and suprasellar extension predicted cure. One patient developed postoperative meningitis that was complicated by hydrocephalus requiring a ventriculoperitoneal shunt. Two patients developed postoperative panhypopituitarism, and 2 patients suffered from CSF leaks, which were treated with lumbar CSF diversion. CONCLUSIONS This paper reports benchmarks for endocrinological cure as well as complications in a large series of purely endoscopic pituitary surgeries by using the most recent consensus criteria. The advantages of extended endonasal approaches are most profound in tumors with suprasellar extension and CS invasion.

Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival

BACKGROUND This prospective, single-center study assesses progression-free survival (PFS) and overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) treated with a single dose of superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) after blood-brain barrier disruption (BBBD). Patients were initially enrolled in our phase I study, for which the primary end point was to determine the safety and maximum tolerated dose of SIACI BV. METHODS Fourteen patients with recurrent GBM were recruited between August 2009 and November 2010 after failing the standard treatment with radiation therapy and temozolomide. None of these patients were previously treated with BV. After receiving a single dose of IA BV (2 to 15 mg/kg), standard IV BV chemotherapy was continued in 12 of 14 patients (86%). The recently updated Response Assessment in Neuro-Oncology Working Group (RANO) criteria were used to evaluate PFS, and the Kaplan-Meier estimator was used to evaluate PFS and OS. RESULTS Using RANO criteria, the median PFS in these patients was 10 months. The median OS estimation for this cohort was 8.8 months. The OS was less than the PFS because 4 patients died without progressing. Toxicity attributed to the IA BV treatment was present in 2 patients (wound dehiscence and rash). Another patient suffered from seizures 1 week after the SIACI procedure; however, this patient had epilepsy before and seizure type/frequency were similar before and after therapy. CONCLUSIONS Our study shows that for patients naïve to BV, a single dose of SIACI BV after BBBD followed by IV BV offers an encouraging outcome in terms of PFS when compared with previous trials using IV BV with and without concomitant irinotecan (CPT-11). Larger phase II trials are warranted to determine whether repeated IA BV alone is superior to IV BV for recurrent GBM.

Protein Phosphatase 2A Mediates Dormancy of Glioblastoma Multiforme-Derived Tumor Stem-Like Cells during Hypoxia

Purpose The hypoxic microenvironment of glioblastoma multiforme (GBM) is thought to increase resistance to cancer therapies. Recent evidence suggests that hypoxia induces protein phosphatase 2A (PP2A), a regulator of cell cycle and cell death. The effects of PP2A on GBM tumor cell proliferation and survival during hypoxic conditions have not been studied. Experimental Design Expression of PP2A subunits and HIF-α proteins was measured in 65 high-grade astrocytoma and 18 non-neoplastic surgical brain specimens by western blotting. PP2A activity was measured by an immunoprecipitation assay. For in vitro experiments, GBM-derived tumor stem cell-like cells (TSCs) were exposed to severe hypoxia produced by either CoCl2 or 1% O2. PP2A activity was inhibited either by okadaic acid or by shRNA depletion of the PP2A C subunit. Effects of PP2A activity on cell cycle progression and cell survival during hypoxic conditions were assessed using flow cytometry. Results In our patient cohort, PP2A activity was positively correlated with HIF-1∝ protein expression (P = 0.002). Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold (P = 0.002). PP2A activity was an independent predictor of survival on multivariable analysis (P = 0.009). In our in vitro experiments, we confirmed that severe hypoxia induces PP2A activity in TSCs 6 hours after onset of exposure. PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activity led to increased cell proliferation, exhaustion of intracellular ATP, and accelerated P53-independent cell death of hypoxic TSCs. Conclusions Our results suggest that PP2A activity predicts poor survival in GBM. PP2A appears to reduce the metabolic demand of hypoxic TSCs and enhances tumor cell survival. Modulation of PP2A may be a potential target for cancer therapy.

Silicate-substituted calcium phosphate ceramic bone graft replacement for spinal fusion procedures.

Study Design. Retrospective study. Objective. To assess the clinical and radiographical outcomes in spinal fusion procedures using silicate-substituted calcium phosphate (Si-CaP). Summary Of Background Data. Si-CaP is a newer-generation synthetic ceramic designed to maximize osteoinduction and osteoconduction. Methods. This is a retrospective analysis of a prospectively collected patient database including 108 patients (204 individual spinal levels). Different surgical procedures performed included 25 anterior cervical discectomy and fusions, 17 posterior cervical fusions, 7 combined anterior and posterior cervical fusions, 10 thoracic fusion surgeries, 18 transforaminal lumbar interbody fusions with 12 axial lumbar interbody fusions, 11 transpsoas discectomy and fusions, and 8 combined thoracolumbar fusion procedures. Si-CaP was used as bone extender without any additional graft material, bone marrow aspirate, or bone morphogenetic protein. Clinical outcomes were assessed using the visual analogue scale (VAS), Oswestry Disability Index, and Neck Disability Index. Fusion was determined by the presence of bony bridging on 2 consecutive sections in at least 2 planes on computed tomographic imaging. Results. At a follow-up of 12 (±4.7) months, 90% of all patients demonstrated radiographical fusion. Fusion rates were highest in the cervical spine (97%) followed by thoracic and lumbar spines (86% and 81%, respectively). There were significant improvements in all clinical outcome measures—Oswestry Disability Index, 11.1 (±10.2) and Neck Disability Index, 9.0 (±11.4); VAS-back, 3.1(±3.0); VAS-leg, 3.5 (±3.6); VAS-neck, 3.7 (±2.5); and VAS-arm 4.0 (±3.2). There was no radiographical loosening of instrumentation due to infection or nonunion in this series, and no subsequent revisions for nonunion were required. Conclusion. Si-CaP is an alternative to autogenous bone graft in spinal arthrodesis procedures. At 12-month follow-up, we detected high levels of bony fusion using Si-CaP in combination with various surgical spinal techniques.

Superselective Intra-Arterial Cerebral Infusion of Novel Agents After Blood–Brain Disruption for the Treatment of Recurrent Glioblastoma Multiforme: A Technical Case Series

Glioblastoma multiforme constitutes the most common primary brain tumor and carries a grim prognosis for patients treated with conventional therapy including surgery, radiation therapy, and chemotherapy. There has been a recent revival of selective intra-arterial delivery of targeted agents for the treatment of glioblastoma multiforme. Because these agents are less toxic and their delivery leads to a higher tumor-drug concentration, this combination may provide a better outcome in patients with high-grade glioma. This article discusses early experiences in patients who received superselective intra-arterial cerebral infusion of bevacizumab, cetuximab, and temozolamide after blood-brain barrier disruption with mannitol.

Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications

The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells.

Anterior cervical discectomy and fusion with a zero-profile integrated plate and spacer device: a clinical and radiological study: Clinical article.

OBJECT Anterior cervical plating decreases the risk of pseudarthrosis following anterior cervical discectomy and fusion (ACDF). Dysphagia is a common complication of ACDF, with the anterior plate implicated as a potential contributor. A zero-profile, stand-alone polyetheretherketone (PEEK) interbody spacer has been postulated to minimize soft-tissue irritation and postoperative dysphagia, but studies are limited. The object of the present study was to determine the clinical and radiological outcomes for patients who underwent ACDF using a zero-profile integrated plate and spacer device, with a focus on the course of postoperative prevertebral soft-tissue thickness and the incidence of dysphagia. METHODS Using a surgical database, the authors conducted a retrospective analysis of all patients who had undergone ACDF between August 2008 and October 2011. All patients received a Zero-P implant (DePuy Synthes Spine). The Neck Disability Index (NDI) and visual analog scale (VAS) scores for arm and neck pain were documented. Dysphagia was determined using the Bazaz criteria. Prevertebral soft-tissue thickness, spinal alignment, and subsidence were assessed as well. RESULTS Twenty-two male and 19 female consecutive patients, with a mean age of 58.4 ± 14.68, underwent ACDF (66 total operated levels) in the defined study period. The mean clinical follow-up in 36 patients was 18.6 ± 9.93 months. Radiological outcome in 37 patients was assessed at a mean follow-up of 9.76 months (range 7.2-19.7 months). There were significant improvements in neck and arm VAS scores and the NDI following surgery. The neck VAS score improved from a median of 6 (range 0-10) to 0 (range 0-8; p < 0.001). The arm VAS score improved from a median of 2 (range 0-10) to 0 (range 0-7; p = 0.006). Immediate postoperative dysphagia was experienced by 58.4% of all patients. Complete resolution was demonstrated in 87.8% of affected patients at the latest follow-up. The overall median Bazaz score decreased from 1 (range 0-3) immediately postoperatively to 0 (range 0-2; p < 0.001) at the latest follow-up. Prevertebral soft-tissue thickness significantly decreased across all levels from a mean of 15.8 ± 4.38 mm to 10.1 ± 2.93 mm. Postoperative lordosis was maintained at the latest follow-up. Mean subsidence from the immediate postoperative to the latest follow-up was 4.1 ± 4.7 mm (p < 0.001). Radiographic fusion was achieved in 92.6% of implants. No correlation was found between prevertebral soft-tissue thickness and Bazaz dysphagia score. CONCLUSIONS A zero-profile integrated plate and spacer device for ACDF surgery produces clinical and radiological outcomes that are comparable to those for nonintegrated plate and spacer constructs. Chronic dysphagia rates are comparable to or better than those for previously published case series.

Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: From bedside to bench

Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival.

Metabolic response of glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab: a proton MR spectroscopic imaging study.

BACKGROUND AND PURPOSE: SIACI of bevacizumab has emerged as a promising novel therapy in the treatment of recurrent GB. This study assessed the potential of 1H-MRS as an adjunctive technique in detecting metabolic changes reflective of antiproliferative effects of targeted infusion of bevacizumab in the treatment of GB. MATERIALS AND METHODS: Eighteen patients enrolled in a phase I/II study of SIACI of bevacizumab for treatment of recurrent GB were included. Concurrent MR imaging and 1H-MRS scans were performed before and after treatment. Five distinct morphologic ROIs were evaluated for structural and metabolic changes on MR imaging and 1H-MRS, which included enhancing, nonenhancing T2 hyperintense signal abnormality, and multiple control regions. Pre- and post-SIACI of bevacizumab peak areas for NAA, tCho, tCr, as well as tCho/tCr and tCho/NAA ratios, were derived for all 5 ROIs and compared using the Wilcoxon signed-rank test. RESULTS: A significant median decrease of 25.99% (range −55.76 to 123.94; P = .006) in tCho/NAA was found post-SIACI of bevacizumab relative to pretreatment values in regions of enhancing disease. A trend-level significant median decrease of 6.45% (range −23.71 to 37.67; P = .06) was noted in tCho/NAA posttreatment in regions of nonenhancing T2-hyperintense signal abnormality. CONCLUSIONS: The results of this 1H-MRS analysis suggest that GB treatment with SIACI of bevacizumab may be associated with a direct antiproliferative effect, as demonstrated by significant reductions of tCho/NAA after the intervention.

Neural stem cells and glioma stem-like cells respond differently to chemotherapeutic drugs: selectivity at the cellular level.

D espite recent refinements of current treatment modalities and the discovery of targets for novel drugs, the prognosis of patients with glioblastoma multiforme (GBM) is still dismal. Since temozolomide (TMZ) given concomitantly with and after radiotherapy became the first-line treatment in newly-diagnosed GBMs, patient survival has significantly increased as shown in prospective clinical trials. In their recently published work, Gong et al from UC Irvine School of Medicine, CA SCIENCE TIMES